Wilms tumor (WT) is the most common renal malignancy of childhood. Despite improvements in the overall survival, relapse occurs in ~15% of patients with favorable histology WT (FHWT). Half of these patients will succumb to their disease. Identifying novel targeted therapies remains challenging in part due to the lack of faithful preclinical in vitro models. Here we establish twelve patient-derived WT cell lines and demonstrate that these models faithfully recapitulate WT biology using genomic and transcriptomic techniques. We then perform loss-of-function screens to identify the nuclear export gene, XPO1, as a vulnerability. We find that the FDA approved XPO1 inhibitor, KPT-330, suppresses TRIP13 expression, which is required for survival. We further identify synergy between KPT-330 and doxorubicin, a chemotherapy used in high-risk FHWT. Taken together, we identify XPO1 inhibition with KPT-330 as a potential therapeutic option to treat FHWTs and in combination with doxorubicin, leads to durable remissions in vivo.

肾母细胞瘤（WT）是儿童最常见的肾脏恶性肿瘤。尽管总生存率有所改善，但组织学 WT (FHWT) 良好的患者中约有 15% 发生复发。这些患者中有一半将死于他们的疾病。识别新型靶向疗法仍然具有挑战性，部分原因是缺乏可靠的临床前体外模型。在这里，我们建立了 12 种源自患者的 WT 细胞系，并证明这些模型使用基因组和转录组技术忠实地重现了 WT 生物学。然后，我们进行功能丧失筛选，将核输出基因XPO1识别为漏洞。我们发现 FDA 批准的 XPO1 抑制剂 KPT-330 可抑制生存所需的TRIP13表达。我们进一步确定了 KPT-330 和阿霉素（一种用于高风险 FHWT 的化疗）之间的协同作用。综上所述，我们确定 KPT-330 抑制 XPO1 作为治疗 FHWT 的潜在治疗选择，并与阿霉素联合使用，可在体内实现持久缓解。